Autism Spectrum Disorders (ASDs) are characterized by deficits in three core domains: social interaction, communication, and repetitive behaviors. ASDs are highly heritable, yet genetic analyses have been largely unsuccessful at identifying genes contributing significantly to the etiology of the disorder. This is likely because ASDs are a collection of heterogenous disorders with multiple genes contributing to various endophenotypes associated with ASD. Recent data suggests that while all three behavioral domains are highly heritable, separate genes may contribute independently to variation in each domain. Thus, investigating mechanisms underlying variation in each domain separately may prove useful for developing treatment strategies for ASD. This proposal focuses on the role of the vasopressin V1a receptor (V1aR) in generating diversity in social behaviors in an animal model and humans. The V1aR plays a critical regulatory role in several behaviors in the social domain, including social recognition, parental care, and social bonding. Three studies have reported genetic associations between polymorphisms in the gene encoding the V1aR (avprla) and autism. Our studies in socially monogamous prairie voles suggest that variation in a microsatellite sequence in the 5'flanking region of the avprla contributes to variation in expression patterns of the V1aR in the brain and in social behavior. This proposal is designed to test four specific hypotheses. First we will test the hypothesis that polymorphisms in the avpM a microsatellite directly contribute to variation in gene expression in the brain using a knock-in mouse approach. We will then use a viral vector-based siRNA approach to directly test the hypothesis that variation in avprla expression in specific brain regions contributes to variation in social behavior. In the final vole study, we will test the hypothesis that variation in avprla expression is a major source of heritable variation in social behavior by first selectively breeding vole lines based on their tendency to form social bonds, and then examining avprla expression in the brain. Finally, we will directly test the hypothesis that polymorphisms in the human AVPR1A contribute to variation in human social cognition. This will be accomplished by testing for associations between four polymorphic microsatellites near the AVPR1A gene and scores on the Schedules for the Assessment of Social Intelligence (SASI) in 200 families with at least one child diagnosed with ASD and in 567 control children. The SASI provides quantitative phenotypic data on facial expression recognition task, face recognition memory task, a gaze monitoring task and a Theory of Mind task. Results from these studies will provide important information on the relationship of variation in the V1aR system and social behavior and may lead to therapies specifically targeting the social deficits in autism.